Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin

Abstract

Parkinson's disease is the second most common neurodegenerative disorder and is characterized by the degeneration of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction has been implicated as an important trigger for Parkinson's disease-like pathogenesis because exposure to environmental mitochondrial toxins leads to Parkinson's disease-like pathology. Recently, multiple genes mediating familial forms of Parkinson's disease have been identified, including PTEN-induced kinase 1 (PINK1; PARK6) and parkin (PARK2), which are also associated with sporadic forms of Parkinson's disease. PINK1 encodes a putative serine/threonine kinase with a mitochondrial targeting sequence. So far, no in vivo studies have been reported for pink1 in any model system. Here we show that removal of Drosophila PINK1 homologue (CG4523; hereafter called pink1) function results in male sterility, apoptotic muscle degeneration, defects in mitochondrial morphology and increased sensitivity to multiple stresses including oxidative stress. Pink1 localizes to mitochondria, and mitochondrial cristae are fragmented in pink1 mutants. Expression of human PINK1 in the Drosophila testes restores male fertility and normal mitochondrial morphology in a portion of pink1 mutants, demonstrating functional conservation between human and Drosophila Pink1. Loss of Drosophila parkin shows phenotypes similar to loss of pink1 function. Notably, overexpression of parkin rescues the male sterility and mitochondrial morphology defects of pink1 mutants, whereas double mutants removing both pink1 and parkin function show muscle phenotypes identical to those observed in either mutant alone. These observations suggest that pink1 and parkin function, at least in part, in the same pathway, with pink1 functioning upstream of parkin. The role of the pink1-parkin pathway in regulating mitochondrial function underscores the importance of mitochondrial dysfunction as a central mechanism of Parkinson's disease pathogenesis.

Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

“…Although nigral degeneration is absent in parkin-deficient mice, they exhibit decreased striatal mitochondrial respiratory capacity and decreased levels of proteins involved in protection from oxidative stress [12]. In Drosophila, deficiency in the mitochondrial kinase PINK1 resembles the pathology associated with mutant parkin, and notably, PINK1 defects can be rescued by wild-type parkin overexpression [62][63][64]. This implies that these proteins function in a common pathway to maintain mitochondrial integrity and function.…”

Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation–Induced Cardiac Proteotoxicity

“…Cellular and mitochondrial ATP contents were measured in freshly prepared whole cell lysates and mitochondrial suspensions from left ventricles (LVs) according to manufacturer's instructions using the ATP Bioluminescence Assay Kit HS II (Roche) 26, 27. Freshly excised LVs were chopped and homogenized using a hand‐driven glass/Teflon potter Elvehjem homogenizer (Wheaton) in cell lysis reagent provided in the kit on ice.…”

RBR Ubiquitin Ligases: Diversification and Streamlining in Animal Lineages

“…This difference may be due to the presence of CG12362, a recent duplicate of ariadne-1 (Marín and Ferrús 2002). On the other hand, parkin mutants are viable, although show some phenotype changes, caused by a general mitochondrial dysfunction (Greene et al 2003;Pesah et al 2004;Clark et al 2006;Park et al 2006;Yang et al 2006). For the other genes, there are no loss-offunction mutants described.…”